Severe affective and behavioral psychiatric disorders affect 5 to 10 million adults in the United States and are the leading cause of disability in North America and Europe. Men and women of all ages and races are at risk for mental illness and for the associated morbidity and societal cost. Although psychopharmacological therapy provides at least partial relief for between 70 to 90% of persons suffering from major depression, bipolar disorder (BPD), obsessive-compulsive disorder (OCD) and panic and other severe anxiety disorders; others are not helped or experience unacceptable medication related side effects. Those experiencing schizophrenia, episodic behavioral disorders, post-traumatic stress disorder (PTSD), addictions, and the behavioral and social disorders associated with autism and pervasive developmental disorders are less often helped by pharmacotherapy or psychotherapy. The economic cost of untreated mental illness is more than 100 billion dollars each year in the United States.
Accordingly, new treatments are clearly needed for those whose symptoms persist and for those not tolerating therapy, as well as to relieve the societal burden created by untreated and under treated mental illness.
Major depression is a serious and persistent medical illness affecting 9.9 million American adults, or approximately 5 percent of the adult population in a given year. Among all medical illnesses, major depression is the leading cause of disability in the U.S. and many other developed countries. About three-fourths of those who experience a first episode of depression will have at least one other episode in their lives and some individuals have several episodes in the course of a year. If untreated, episodes commonly last anywhere from six months to a year. Left untreated, depression can lead to suicide.
Treatment typically includes medications, psychotherapy, and electroconvulsive therapy (ECT) used singly or in combination. Although mild to moderate depression can often be treated successfully with medications or psychotherapy used alone, severe depression usually requires a combination of psychotherapy and medication. ECT is highly effective for treatment resistant or treatment intolerant severe depression and to relieve symptoms such as psychosis or thoughts of suicide. However, ECT often requires repeated therapies and can cause persistent and troubling memory disturbances.
Bipolar disorder is another other common major psychiatric disorders that may be treatment resistant. Bipolar disorder is a chronic disorder that affects 2.3 million adult Americans. Bipolar disorder is characterized by episodes of mania and depression that can last from days to months. Persons with bipolar disorder usually require lifelong treatment, and recovery between episodes is often poor. Generally, those who suffer from bipolar disorder have symptoms of both mania and depression (sometimes at the same time). Medications are available to treat depression or mania and provide mood stabilization. However, most persons with bipolar disorder require multiple medications to achieve symptom relief. Thus, persons with bipolar disease are at risk for medication related side effects that prompt some to discontinue therapy. Others who are compliant with therapy do not achieve complete symptom relief.
Obsessive-Compulsive Disorder (OCD) affects 2 to 3% of the population as confirmed in the U.S. and international epidemiological studies, and is two to three times more common than schizophrenia and bipolar disorder. Obsessions and compulsive behaviors can cause suffering and severe restrictions on life activities. Response to treatment varies from person to person. Most people treated with effective medications find their symptoms reduced by about 40 percent to 50 percent. Although such symptom relief is welcome, freedom from symptoms is rarely achieved and only a small number of people are fortunate to go into total remission. Only one fifth of patients achieve full remission within one decade of the onset of the illness and two-thirds continue to experience symptoms despite treatment with selective serotonin reuptake inhibitor drugs (SSRIs) and the use of behavior therapy.
Some persons with chronic, treatment resistant mental illness have turned to surgical therapies. Frontal lobotomy was championed in the late 1930s to the 1970s. Although effective in some cases, the surgery was crude, not standardized and involved destruction of a large region of the frontal lobe. The procedure was largely abandoned because of unacceptable surgical complications and because of ethical violations in its application. A few centers continued to offer surgical therapy to the most devastated patients. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1977) indicated that more than half of 400 surgeries performed annually between 1971 and 1973 for psychiatric indications were efficacious, and there is reason to believe efficacy has improved since then.
Recently, neurosurgeons have developed more precise surgical procedures to treat psychiatric disorders, including depression and, more commonly, obsessive-compulsive disorder. The majority of these procedures involve targeted ablative procedures. In these refractory patients, stereotactic surgical interventions performed include subcaudate tractotomy, limbic leucotomy, capsulotomy, and cingulotomy. Cingulotomy is the most commonly performed procedure. Twentyfive to 30% of patients treated with cingulotomy experience improvement at more than 2 years follow-up. However, these procedures are associated with risks including changes in personality and development of epilepsy. Other adverse effects include frontal lobe deficit in as many as 30% with fatigue, emotional blunting, emotional incontinence, indifference, low initiative, disinhibition and impaired judgment. These procedures carry the risk that the lesion will be malpositioned, which may require repeated surgery to extend the size of the lesion. Thus, concerns about safety and the irreversibility of surgical procedures remain.
Due to the limited response to lesion- based surgery and concerns about adverse effects, some investigators have turned to electrical stimulation therapy. Building on the experience from essential tremor and Parkinson's Disease, investigators have utilized commercially available deep brain stimulators implanted in the anterior internal capsule bilaterally and have reported symptomatic improvement in OCD. However, because of the stimulation requirements for clinical response (4 to 10.5V, impedance 700 ohms, pulse width 210 microseconds, 100 Hz frequency) the stimulator battery requires replacement every 5 to 12 months, limiting patient acceptance for this therapy.
The neuroanatomical base for many psychiatric disorders is better understood because of advances in functional neuroimaging, such as Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI), Functional MRI (fMRI), and Magnetoencephalography (MEG). In addition, clinical observations after destructive brain lesions identify regions subserving specific aspects of behavior and affect. The cingulate cortex is a large structure around the rostrum of the corpus callosum that has extensive projections with the amygdala, periaqueductal grey, ventral striatum, orbitofrontal and anterior insular cortices. This structure and its interconnections are intimately involved in mood and behavior. Dysfunction of the cingulate and disruption of its connections has been implicated in a number of psychiatric disorders. As noted above, cingulotomy is the most common psychosurgery procedure for major depression and obsessive-compulsive disorder. This procedure is effective for many but carries considerable risk for post-surgical changes in personality and motivation, and for post-operative epilepsy.
The size and complexity of the cingulate cortex poses a challenge in targeting the region responsible for specific psychiatric and behavioral disorders. The cingulate is divided functionally into regions concerned with affect and cognition. Affect is mediated in cingulate regions 25, 33 and rostral area 24 that are extensively interconnected to the amygdala and periaqueductal grey, as well as autonomic brainstem nuclei. The cognitive division resides in caudal areas 24′ and 32′, and in cingulate motor areas in the cingulate sulcus and nociceptive cortex. Individuals with disturbances to the cingulate cortex, such as those with cingulate onset epilepsy, often display sociopathic behavior. Elevated anterior cingulate activity may contribute to tics, obsessive-compulsive behaviors and aberrant social behavior. Reduced cingulate activity can contribute to schizophrenia, behavioral disorders such as akinetic mutism, diminished self-awareness and depression, motor neglect and impaired initiation of movement, reduced pain response and abnormal social behavior.
There is a need for a responsive implantable system capable of ameliorating the symptoms of, and in some cases the underlying causes of, various psychiatric disorders.